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Mass spectrometry imaging (MSI) or imaging mass spectrometry (IMS) is a technique used in mass spectrometry to visualize the spatial distribution of chemical compositions e.g. compounds, biomarkers, metabolites, peptides or proteins by their molecular masses. Although widely used traditional methodologies like radiochemistry and immunohistochemistry achieve the same goal as MSI, they are limited in their abilities to analyze multiple samples at once, and can prove to be lacking if researchers do not have prior knowledge of the samples being studied.[1] Most common ionization technologies in the field of MSI are DESI imaging, MALDI imaging and secondary ion mass spectrometry imaging (SIMS imaging).[2][3]

History

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More than 50 years ago, IMS was introduced using secondary ion mass spectrometry (SIMS). However, it was the pioneering work of Richard Caprioli and colleagues in the late 1990s, demostrating how matriz-assisted laser desorption/ionization (MALDI) could be applied to visualize large biomolecules (as proteins and lipids) in cells and tissue to reveal the function of these molecules and how function is changed by diseases like cancer, which led to the widespread use of IMS. Nowadays, different ionization techniques have been used, including SIMS, MALDI and desorption electrospray ionization (DESI), as well as other technologies. Still, MALDI is the current dominant technology with regard to clinical and biological applications of MSI.[4]

Operation Principle

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The MSI is based on the spatial distribution of the sample. Therefore, the operation principle depends on the technique that is used to obtain the spatial information. The two techniques used in MSI are: microprobe and microscope.[5]

Microprobe

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This technique is performed using a focused ionization beam to analyze a specific region of the sample by generating a mass spectrum. The mass spectrum is stored along with the spatial coordination where the measurement took place. Then, a new region is selected and analyzed by moving the sample or the ionization beam. This steps are repeated until the entire sample has been scanned. By coupling all individual mass spectra, a distribution map of intensities as a function of x and y locations can be plotted. As a result reconstructed molecular images of the sample are obtained.[5]

Microscope

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In this technique, a 2D position-sensitive detector is used to measure the spatial origin of the ions generated at the sample surface by the ion optics of the instruments. The resolution of the spatial information will depend on the magnification of the microscope, the quality of the ions optics and the sensitivity of the detector. A new region still need to be scanned. but the number of positions drastically reduces. The limitation of this mode is the finite depth of vision present with all microscopes[5].

Most of the information below is related with the microprobe technique, since this method is the most simple and common used for MSI.

Ion Source Dependence

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The Ionization techniques available for IMS are suited to different applications. Some of the criteria for choosing the ionization method are the sample preparation requirement and the parameters of the measurement, as resolution, mass range and sensitivity. Based on that, the most common used ionization method are MALDI, SIMS AND DESI which are described below. Still, other minor techniques used are laser ablation electrospray ionization (LAESI) and laser-ablation-inductively coupled plasma (LA-ICP).

SIMS imaging

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Secondary ion mass spectrometry (SIMS) is used to analyze solid surfaces and thin films by sputtering the surface with a focused primary ion beam and collecting and analyzing ejected secondary ions. There are many different sources for a primary ion beam. However, the primary ion beam must contain ions that are at the higher end of the energy scale. Some common sources are: Cs+, O2+, O, Ar+ and Ga+.[6] SIMS imaging is performed in a manner similar to electron microscopy; the primary ion beam is emitted across the sample while secondary mass spectra are recorded.[7] SIMS proves to be advantageous in providing the highest image resolution but only over small area of samples.[8] More, this technique is widely regarded as one of the most sensitive forms of mass spectrometry as it can detect elements as small as 10−6-10−9.[9]

Multiplexed ion beam imaging (MIBI) is a SIMS method that uses metal isotope labeled antibodies to label compounds in biological samples.[10]

Developments within SIMS: Some chemical modifications have been made within SIMS to increase the efficiency of the process. There are currently two separate techniques being used to help increase the overall efficiency by increasing the sensitivity of SIMS measurements: matrix-enhanced SIMS (ME-SIMS) - This has the same sample preparation as MALDI does as this simulates the chemical ionization properties of MALDI. ME-SIMS does not sample nearly as much material. However, if the analyte being tested has a low mass value then it can produce a similar looking spectra to that of a MALDI spectra. ME-SIMS has been so effective that it has been able to detect low mass chemicals at sub cellular levels that was not possible prior to the development of the ME-SIMS technique.[3] The second technique being used is called sample metallization (Meta-SIMS) - This is the process of gold or silver addition to the sample. This forms a layer of gold or silver around the sample and it is normally no more than 1-3 nm thick. Using this technique has resulted in an increase of sensitivity for larger mass samples. The addition of the metallic layer also allows for the conversion of insulating samples to conducting samples, thus charge compensation within SIMS experiments is no longer required.[11]

MALDI imaging

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Mouse kidney: (a) MALDI spectra from the tissue. (b) H&E stained tissue. N-glycans at m/z = 1996.7 (c) is located in the cortex and medulla while m/z = 2158.7 (d) is in the cortex, (e) An overlay image of these two masses, (f) untreated control tissue.[12]
Main article: MALDI imaging

Matrix-assisted laser desorption ionization can be used as a mass spectrometry imaging technique for relatively large molecules.[3] It has recently been shown that the most effective type of matrix to use is an ionic matrix for MALDI imaging of tissue. In this version of the technique the sample, typically a thin tissue section, is moved in two dimensions while the mass spectrum is recorded.[13] Although MALDI has the benefit of being able to record the spatial distribution of larger molecules, it comes at the cost of lower resolution than the SIMS technique. The limit for the lateral resolution for most of the modern instruments using MALDI is 20 m. MALDI experiments commonly use either an Nd:YAG (355 nm) or N2 (337 nm) laser for ionization.[3]

Pharmacodynamics and toxicodynamics in tissue have been studied by MALDI imaging.[14]

DESI imaging

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Desorption electrospray Ionization is a less destructive technique, which couples simplicity and rapid analysis of the sample. The sample is sprayed with an electrically charged solvent mist at an angle that causes the ionization and desorption of various molecular species. Then, two-dimensional maps of the abundance of the selected ions in the surface of the sample in relation with the spatial distribution are generated. [15][8]This technique is applicable to solid, liquid, frozen and gaseous samples. Moreover, DESI allows analyzing a wide range of organic and biological compounds, as animal and plant tissues and cell culture samples, without complex sample preparation[4][8] Although, this technique has the poorest resolution among other, it can create high-quality image from a large area scan, as a whole body section scanning. [8]

Comparative between the Ionization Techniques

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Comparison of typical parameters among IMS techniques[8]
Ionization Source Type of Ionization Analytes Spatial Resolution Mass Range
SIMS Ion gun Hard Elemental ions, small molecules, lipids <10 m 0-1000 Da
MALDI UV laser beam Soft Lipids, peptide, proteins 20 m 0-100 000 Da
DESI Solvent Spray Soft Small molecules, lipids, peptides 100 m 0-2000 Da

Combination of Various IMS Techniques and other imaging techniques

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Combining various IMS techniques can be beneficial, since each particular technique has its own advantage. For example, when information regards both proteins and lipids are necessary in the same tissue section, performing DESI to analyze the lipid, followed by MALDI to obtain information about the peptide, and finalize applying a stain (haematoxylin and eosin) for medical diagnosis of the structural characteristic, of the tissue.[8] Among IMS with other imaging techniques, IMS with fluorescence staining and IMS with magnetic resonance imaging (MRI) can be highlighted. Fluorescence staining can give information of the appearance of some proteins present in any process inside a tissue, while IMS may give information about the molecular changes presented in that process. Combining both techniques, multimodal picture or even 3D images of the distribution of different molecules can be generated.[8] In contrast, MRI with IMS combines the continuous 3D representation of MRI image with detailed structural representation using molecular information from IMS. Even though, IMS itself can generate 3D images, the picture is just part of the reality due to the depth limitation in the analysis, while MRI provides, for example, detailed organ shape with additional anatomical information. This coupled technique can be beneficial for cancer precise diagnosis and neurosurgery.[8]

Data Processing

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Standard data format for mass spectrometry imaging datasets

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An useful data format for IMS is imML data format, because several imaging MS software tools support it. The advantage of this format is the flexibility to exchange data between different instruments and data analysis softwares[16]. All necessary information for evaluating and implementing imzML can be found at http://www.imzML.org.

Software

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There are many free software packages available for visualization and mining of imaging mass spectrometry data. Converters from Thermo Fisher format, Analyze format, GRD format and Bruker format to imzML format were developed by the Computis project. Some software modules are also available for viewing mass spectrometry images in imzML format: Biomap] (Novartis, free), Datacube Explorer (AMOLF, free),[17] EasyMSI (CEA), Mirion (JLU), MSiReader (NCSU, free)[18] and SpectralAnalysis.[19]

For processing .imzML files with the free statistical and graphics language R, a collection of R scripts is available, which permits parallel-processing of large files on a local computer, a remote cluster or on the Amazon cloud.[20]

Another free statistical package for processing imzML and Analyze 7.5 data in R exists, Cardinal .[21]

Applications

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A remarkable ability of IMS is to find out the localization of biomolecules in tissues, even though there are no previous information about them. This feature has made IMS an unique tool for clinical research and pharmacological research. It provides information about biomolecular changes related with diseases by tracking proteins, lipids, and cell metabolism. For example, identifying biomakers by IMS can show detailed cancer diagnosis. In addition, low cost imaging for pharmaceuticals studies can be acquired, such as images of molecular signatures that would be indicative of treatment response for a specific drug.[22][23]

Advantages, Challenges and Limitations

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The main advantage of MSI for studying the molecules location and distribution within the tissue is that this analysis can provide either greater selectivity, more information or more accuracy. Moreover, this tool requires less investment of time and resources for similar results.[24]

Current Complexity for MSI[24]
Difficult/Why? Readily Performed
Proteomics: mass range limited Drug and metabolite
Free drug from total: Does break interactions On-tissue quantification
Terminal sampling required: no monitoring Pathology support
Sub-cellular: instrument limitations Studying unantecipated outcomes
Clinical samples: sample collection Biomarkers analysis
Antibodies Comparing tissues for unkown
Blood brain barriers/tumours

References

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  1. ^ Monroe E, Annangudi S, Hatcher N, Gutstein H, Rubakhin S, Sweedler J (2008). "SIMS and MADLI MS Imaging of the spinal cord". Proteomics. 8 (18): 3746–3754. doi:10.1002/pmic.200800127.
  2. ^ Rohner T, Staab D, Stoeckli M (2005). "MALDI mass spectrometric imaging of biological tissue sections". Mechanisms of Ageing and Development. 126 (1): 177–185. doi:10.1016/j.mad.2004.09.032. PMID 15610777.
  3. ^ a b c d McDonnell LA, Heeren RM (2007). "Imaging mass spectrometry". Mass spectrometry reviews. 26 (4): 606–43. Bibcode:2007MSRv...26..606M. doi:10.1002/mas.20124. PMID 17471576.
  4. ^ a b Addie, Ruben D.; Balluff, Benjamin; Bovée, Judith V. M. G.; Morreau, Hans; McDonnell, Liam A. "Current State and Future Challenges of Mass Spectrometry Imaging for Clinical Research". Analytical Chemistry. 87 (13): 6426–6433. doi:10.1021/acs.analchem.5b00416.
  5. ^ a b c McDonnell, Liam A.; Heeren, Ron M.A. (2007-07-01). "Imaging mass spectrometry". Mass Spectrometry Reviews. 26 (4): 606–643. doi:10.1002/mas.20124. ISSN 1098-2787.
  6. ^ Amstalden Van Hove E, Smith D, Heeren R (2010). "A concise review of mass spectrometry imaging". Journal of Chromatography A. 1217 (25): 3946–3954. doi:10.1016/j.chroma.2010.01.033.
  7. ^ Penner-Hahn, James E. (2013). "Chapter 2. Technologies for Detecting Metals in Single Cells. Section 2.1, Secondary Ion Mass Specctrometry". In Banci, Lucia (Ed.) (ed.). Metallomics and the Cell. Metal Ions in Life Sciences. Vol. 12. Springer. doi:10.1007/978-94-007-5561-1_2. ISBN 978-94-007-5560-4.electronic-book ISBN 978-94-007-5561-1 ISSN 1559-0836electronic-ISSN 1868-0402
  8. ^ a b c d e f g h Bodzon-Kulakowska, Anna; Suder, Piotr (2016-01-01). "Imaging mass spectrometry: Instrumentation, applications, and combination with other visualization techniques". Mass Spectrometry Reviews. 35 (1): 147–169. doi:10.1002/mas.21468. ISSN 1098-2787.
  9. ^ Chabala J, Soni K, Li J, Gavlirov K, Levi-Setti R (1995). "High resolution chemical imaging with scanning ion probe SIMS": 191–212. {{cite journal}}: Cite journal requires |journal= (help)
  10. ^ Angelo, Michael; Bendall, Sean C; Finck, Rachel; Hale, Matthew B; Hitzman, Chuck; Borowsky, Alexander D; Levenson, Richard M; Lowe, John B; Liu, Scot D; Zhao, Shuchun; Natkunam, Yasodha; Nolan, Garry P (2014). "Multiplexed ion beam imaging of human breast tumors". Nature Medicine. 20 (4): 436–442. doi:10.1038/nm.3488. ISSN 1078-8956. PMC 4110905. PMID 24584119.
  11. ^ Delcorte A, Befahy S, Poleunis C, Troosters M, Bertrand P. "Improvements of metal adhesion to silicon films: a ToF-SIMS study". {{cite journal}}: Cite journal requires |journal= (help)
  12. ^ Powers, Thomas W.; Neely, Benjamin A.; Shao, Yuan; Tang, Huiyuan; Troyer, Dean A.; Mehta, Anand S.; Haab, Brian B.; Drake, Richard R. (2014). "MALDI Imaging Mass Spectrometry Profiling of N-Glycans in Formalin-Fixed Paraffin Embedded Clinical Tissue Blocks and Tissue Microarrays". PLoS ONE. 9 (9): e106255. Bibcode:2014PLoSO...9j6255P. doi:10.1371/journal.pone.0106255. ISSN 1932-6203. PMC 4153616. PMID 25184632.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ Chaurand P, Norris JL, Cornett DS, Mobley JA, Caprioli RM (2006). "New developments in profiling and imaging of proteins from tissue sections by MALDI mass spectrometry". J. Proteome Res. 5 (11): 2889–900. doi:10.1021/pr060346u. PMID 17081040.
  14. ^ Patel, Ekta (1 January 2015). "MALDI-MS imaging for the study of tissue pharmacodynamics and toxicodynamics". Bioanalysis. 7 (1): 91–101. doi:10.4155/bio.14.280. Retrieved 24 February 2015.
  15. ^ Nilsson, Anna; Goodwin, Richard J. A.; Shariatgorji, Mohammadreza; Vallianatou, Theodosia; Webborn, Peter J. H.; Andrén, Per E. (2015-02-03). "Mass Spectrometry Imaging in Drug Development". Analytical Chemistry. 87 (3): 1437–1455. doi:10.1021/ac504734s. ISSN 0003-2700.
  16. ^ A. Römpp; T. Schramm; A. Hester; I. Klinkert; J.P. Both; R.M.A. Heeren; M. Stoeckli; B. Spengler (2011). "Chapter imzML: Imaging Mass Spectrometry Markup Language: A Common Data Format for Mass Spectrometry Imaging in Data Mining in Proteomics: From Standards to Applications". Methods in Molecular Biology, Humana Press, New York. Vol. 696. pp. 205–224.
  17. ^ Klinkert, I.; Chughtai, K.; Ellis, S. R.; Heeren, R. M. A. (2014). "Methods for Full Resolution Data Exploration and Visualization for Large 2D and 3D Mass Spectrometry Imaging Datasets". International Journal of Mass Spectrometry. 362: 40–47. Bibcode:2014IJMSp.362...40K. doi:10.1016/j.ijms.2013.12.012.
  18. ^ Robichaud, G.; Garrard, K. P.; Barry, J. A.; Muddiman, D. C. (2013). "MSiReader: An Open-Source Interface to View and Analyze High Resolving Power MS Imaging Files on Matlab Platform". Journal of the American Society for Mass Spectrometry. 24 (5): 718–721. Bibcode:2013JASMS..24..718R. doi:10.1007/s13361-013-0607-z. PMC 3693088. PMID 23536269.
  19. ^ Race, A. M.; Palmer, A. D.; Dexter, A.; Steven, R. T.; Styles, I. B.; Bunch, J. (2016). "SpectralAnalysis: software for the masses". Analytical Chemistry. 88 (19): 9451–9458. doi:10.1021/acs.analchem.6b01643. PMID 27558772.
  20. ^ Gamboa-Becerra, Roberto; Ramírez-Chávez, Enrique; Molina-Torres, Jorge; Winkler, Robert (2015-07-01). "MSI.R scripts reveal volatile and semi-volatile features in low-temperature plasma mass spectrometry imaging (LTP-MSI) of chilli (Capsicum annuum)". Analytical and Bioanalytical Chemistry. 407 (19): 5673–5684. doi:10.1007/s00216-015-8744-9. PMID 26007697.
  21. ^ Bemis, Kyle D.; Harry, April; Eberlin, Livia S.; Ferreira, Christina; van de Ven, Stephanie M.; Mallick, Parag; Stolowitz, Mark; Vitek, Olga (2015-03-15). "Cardinal: an R package for statistical analysis of mass spectrometry-based imaging experiments". Bioinformatics. 31 (14): 2418–2420. doi:10.1093/bioinformatics/btv146. PMC 4495298. PMID 25777525.
  22. ^ Addie, Ruben D.; Balluff, Benjamin; Bovée, Judith V. M. G.; Morreau, Hans; McDonnell, Liam A. (2015-07-07). "Current State and Future Challenges of Mass Spectrometry Imaging for Clinical Research". Analytical Chemistry. 87 (13): 6426–6433. doi:10.1021/acs.analchem.5b00416. ISSN 0003-2700.
  23. ^ Aichler, Michaela; Walch, Axel (2015/04). "MALDI Imaging mass spectrometry: current frontiers and perspectives in pathology research and practice". Laboratory Investigation. 95 (4): 422–431. doi:10.1038/labinvest.2014.156. ISSN 1530-0307. {{cite journal}}: Check date values in: |date= (help)
  24. ^ a b Nilsson, Anna; Goodwin, Richard J. A.; Shariatgorji, Mohammadreza; Vallianatou, Theodosia; Webborn, Peter J. H.; Andrén, Per E. (2015-02-03). "Mass Spectrometry Imaging in Drug Development". Analytical Chemistry. 87 (3): 1437–1455. doi:10.1021/ac504734s. ISSN 0003-2700.
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